This invention is concerned with a pharmaceutical iodophor preparation, its use and its manufacture. Apart from iodine with its longstanding disadvantages, iodophor preparations are known and commercially available which have considerable advantages over iodine, iodine tinctures etc. Attention is drawn, in particular, to polyvinylpyrrolidone iodine (PVP iodine), a preparation which is commercially available in a variety of forms and has recognizedly good microbicidal properties.
However, such iodophor preparations, including in particular PVP iodine, also have disadvantages which are important. These disadvantages relate primarily to the preparations' storage stability, their reliable effectiveness over an extended period and their reproducibility, i.e. their manufacture to a consistently good effective quality.
There has therefore been no shortage of formulations adapted to eliminate these disadvantages. For example, U.S. Pat. No. 4,113,857 proposes a process for manufacturing iodophor preparations, in which it is stressed that the preparation should not contain any iodide ion, this being based on the recognition that the presence of iodide ion should be regarded as a contamination leading to a reduction of the free, elementary, caustic iodine. According to this patent it is therefore important to produce iodophor preparations which are free of iodide ion.
Another method of improving iodophor preparations is described in U.S. Pat. No. 4,271,149. According to this patent preparations which are stable during storage are produced by the addition of iodate ion in an amount of 0.005% to 0.2%, preferably 0.05 to 0.1%, to the preparation and the control of the preparations' pH-value to within pH 5 to 7. In this patent great importance is attached to the iodide content required to achieve stability. This is illustrated by the results given in U.S. Pat. No. 4,271,149, especially for the preparations having a high iodide content. It is important to note that U.S. Pat. No. 4,271,149, does not distinguish between available iodine and free, equilibrium iodine, a distinction that, in pharmaceutical terms, is critical to the questions of efficacy and stability. Furthermore the preparations of Winicov have not proved to be sufficiently stable for pharmaceutical purposes.
From DE 27 18 385 a biocide substance is known, for example PVP iodine, for which the presence of an oxidizing agent is essential in order to oxidize iodide to yield free iodine, which is then directly complex-bound, whereby the oxidizing agent prevents the reforming of iodide from iodine up to a stable balance. This target is not achieved.
From DE 24 38 594 a disinfectant is known, which for instance contains PVP iodine, but which contains hydrogen peroxide as an essential additive; this leads to an essentially reduced iodine content, but not to a stable preparation.
In FR 745 693 a well known iodine bandage is described for which component ratios do not matter at all.
From the GB 2 024 012A a medical dressing is known which when applied to a wound gives off gaseous oxygen based on a concentration of a peroxide and decomposing agent suitable for it, for instance potassium iodide. Such a dressing has no relevance to the present invention.
In U.S. Pat. No. 4,125,602 a process for manufacturing an iodophor is described which aims at an economical and quick cycle of operations. The process produces a granulate with uniform particle size. This publication does not contain any suggestions as to how the disadvantages of PVP-iodine preparations can be avoided.
From U.S. Pat. No. 4,113,857 iodophors such as PVP iodine are known, in which iodide ions are considered disadvantageous. The aim is to produce iodide-free preparations which are not contaminated by iodide ions.
U.S. Pat. Nos. 2,706,701, 3,028,300, 4,038,476, 4,130,640, 4,214,059, 4,320,114, 4,427,631 and 4,526,751 all describe methods of preparing povidone iodine compositions. None, however, provide solutions to the problems of instability, reliability and reproducibility faced by the present inventors. Furthermore, the importance of the stability of free, equilibrium iodine levels, especially in pharmaceutical terms, is not discussed.
For a full and proper understanding of the present invention, it is important to distinguish in the present preparations between free, equilibrium iodine (the concentration of which may be measured potentiometrically) and available iodine (the concentration of which may be measured by titration).
Povidone iodine solutions contain non-complexed, otherwise known as free, equilibrium iodine, and complexed iodine, in which the iodine is complexed with povidone. The combination of complexed and free iodine constitutes available (titratable) iodine.
For antiseptic/disinfectant purposes it is the level of free, equilibrium iodine (not available iodine) that determines the bactericidal properties of povidone iodine. The higher the level of free iodine, the better the bactericidal effect within a given time span. Of course, the level of free iodine must not become too high, otherwise the unwanted, side-effects of free iodine will become apparent.
Thus it is the aim of the present invention to provide a povidone iodine preparation having a narrowly defined and stable level of free iodine.
By contrast, Winicov in U.S. Pat. No. 4,271,149 is concerned with the stability of available iodine levels. The stability of free iodine levels is not addressed nor is the pharmaceutical importance of these (free iodine) levels. As will be seen in the experimental section of the present specification, the free iodine levels of Winicov's preparations are not stable.